tbuckley/cabot-search huggingface dataset:
Posoleucel, an Allogeneic, Off-the-Shelf Multivirus-Specific T-Cell Therapy, for the Treatment of Refractory Viral Infections in the Post-HCT Setting
Authors: Thomas Pfeiffer, Ifigeneia Tzannou, Mengfen Wu, Carlos Ramos, Ghadir Sasa, Caridad Martinez, Premal Lulla, Robert A. Krance, Lauren Scherer, Daniel Ruderfer, Swati Naik, Claire Bocchini, Iain P. Fraser, Badrish Patel, Dany Ward, Tao Wang, Helen E. Heslop, Ann M. Leen, Bilal Omer
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Viral infections are a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). In the absence of safe and effective antiviral treatments, virus-specific T cells have emerged as a promising therapeutic option. Posoleucel is a multivirus-specific T-cell therapy for off-the-shelf use against six viral infections that commonly occur in allo-HCT recipients: adenovirus, BK virus (BKV), cytomegalovirus, Epstein–Barr virus, human herpes virus-6, and JC virus. Patients and Methods: We conducted an open-label, phase II trial to determine the feasibility and safety of posoleucel in allo-HCT recipients infected with one or more of these viruses. Infections were either unresponsive to or patients were unable to tolerate standard antiviral therapies. Fifty-eight adult and pediatric patients were enrolled and treated. Results: Posoleucel was well tolerated, with no cytokine release syndrome or other infusion-related toxicities; two patients (3.4%) developed Grade 2 and one patient (1.7%) Grade 3 GvHD during the trial. The overall response rate 6 weeks after the first posoleucel infusion was 95%, with a median plasma viral load reduction of 97%. Of the 12 patients who had two or more target viral infections identified at study entry, 10 (83%) had a clinical response for all evaluable viruses. Of the 23 patients treated for refractory BKV-associated hemorrhagic cystitis, 74% had resolution of symptoms and macroscopic hematuria by 6 weeks post-infusion. Conclusions: In this open-label trial, treatment of refractory viral infections/disease in allo-HCT recipients with posoleucel was feasible, safe, and effective.
Risk of Esophageal and Gastric Cancer After Bariatric Surgery
Authors: Andrea Lazzati, Tigran Poghosyan, Marwa Touati, Denis Collet, Caroline Gronnier
Journal: JAMA Surgery (2023)

Bariatric surgery has been associated with a reduced risk of cancer in individuals with obesity. The association of bariatric surgery with esophageal and gastric cancer is still controversial, however.
Estimation of Out-of-Pocket Costs for Guideline-Directed Medical Therapy for Heart Failure Under Medicare Part D and the Inflation Reduction Act
Authors: Micah Johnson, Rahul K. Nayak, Lauren Gilstrap, Stacie B. Dusetzina
Journal: JAMA Cardiology (2023)

This cross-sectional study estimates out-of-pocket costs of heart failure with reduced ejection fraction medication regimens in Medicare Part D under current law and the Inflation Reduction Act.
Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension
Authors: Jude Moutchia, Robyn L. McClelland, Nadine Al-Naamani, Dina H. Appleby, Kristina Blank, Dan Grinnan, John H. Holmes, Stephen C. Mathai, Jasleen Minhas, Corey E. Ventetuolo, Roham T. Zamanian, Steven M. Kawut
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: The six-minute walk distance is an important clinical and research metric in pulmonary arterial hypertension; however, there is no consensus about what minimal change in six-minute walk distance is clinically significant. Objectives: We aimed to determine the minimal clinically important difference in the six-minute walk distance. Methods: We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for pulmonary arterial hypertension that were submitted to the United States Food and Drug Administration to derive minimal clinically important differences in the six-minute walk distance. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in six-minute walk distance to the change in the Medical Outcomes Survey Short Form Physical Component Score. Measurements and Main Results: The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with pulmonary arterial hypertension respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 m (95% CI: 27, 38) which was almost identical to that in the validation sample (36 m [95% CI: 29, 43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class. Conclusion: We estimated a six-minute walk distance minimal clinically important difference of ~ 33 m for adults with pulmonary arterial hypertension. Our findings can be applied to the design of clinical trials of therapies for pulmonary hypertension.
Correction: Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology
Authors: Ankit Verma, Anna Shteinfer-Kuzmine, Nikita Kamenetsky, Srinivas Pittala, Avijit Paul, Edna Nahon Crystal, Alberto Ouro, Vered Chalifa-Caspi, Swaroop Kumar Pandey, Alon Monsonego, Noga Vardi, Shira Knafo, Varda Shoshan-Barmatz
Journal: Translational Neurodegeneration (2023)
Regulatory mucosa-associated invariant T cells controlled by β1 adrenergic receptor signaling contribute to hepatocellular carcinoma progression
Authors: Sicheng Fu, Muziying Liu, Chenwen Zhu, Huimin Zhang, Changfeng Zhao, Yaping Xie, Guanghou Chen, Daping Sheng, Jun Pan, Ziqing He, Ying Dai, Yufeng Gao, Xiaomei Li, Lijian Chen, Yeben Qian, Tengchuan Jin, Cheng Sun, Zhigang Tian, Hua Wang, Li Bai
Journal: Hepatology (2023)

Background and Aims: The innate-like mucosa-associated invariant T (MAIT) cells are enriched in human liver and have been linked to human HCC. However, their contributions to the progression of HCC are controversial due to the heterogeneity of MAIT cells, and new MAIT cell subsets remain to be explored. Approach and Results: Combining single cell RNA sequencing (scRNA-seq) and flow cytometry analysis, we performed phenotypic and functional studies and found that FOXP3 + CXCR3 + MAIT cells in HCC patients were regulatory MAIT cells (MAITregs) with high immunosuppressive potential. These MAITregs were induced under Treg-inducing condition and predominantly from FOXP3 − CXCR3 + MAIT cells, which displayed mild Treg-related features and represented a pre-MAITreg reservoir. In addition, the induction and function of MAITregs were promoted by β1 adrenergic receptor signaling in pre-MAITregs and MAITregs, respectively. In HCC patients, high proportion of the intratumoral MAITregs inhibited antitumor immune responses and was associated with poor clinical outcomes. Conclusions: Together, we reveal an immunosuppressive subset of MAIT cells in HCC patients that contributes to HCC progression, and propose a control through neuroimmune crosstalk.
Organelle stress and alterations in interorganelle crosstalk during liver fibrosis
Authors: Saloni Sinha, Nora Hassan, Robert E. Schwartz
Journal: Hepatology (2023)

The synchronous functioning and quality control of organelles ensure cell survival and function and are essential for maintaining homeostasis. Prolonged exposure to stressors (viruses, bacteria, parasitic infections, alcohol, drugs) or genetic mutations often disrupt the functional integrity of organelles which plays a critical role in the initiation and progression of several diseases including chronic liver diseases. One of the most important pathologic consequences of chronic liver diseases is liver fibrosis, characterized by tissue scarring due to the progressive accumulation of extracellular matrix components. Left untreated, fibrosis may advance to life-threatening complications such as cirrhosis, hepatic decompensation, and HCC, which collectively accounts for ∼1 million deaths per year worldwide. Owing to the lack of treatment options that can regress or reverse cirrhosis, liver transplantation is currently the only available treatment for end-stage liver disease. However, the limited supply of usable donor organs, adverse effects of lifelong immunosuppressive regimes, and financial considerations pose major challenges and limit its application. Hence, effective therapeutic strategies are urgently needed. An improved understanding of the organelle-level regulation of fibrosis can help devise effective antifibrotic therapies focused on reducing organelle stress, limiting organelle damage, improving interorganelle crosstalk, and restoring organelle homeostasis; and could be a potential clinical option to avoid transplantation. This review provides a timely update on the recent findings and mechanisms covering organelle-specific dysfunctions in liver fibrosis, highlights how correction of organelle functions opens new treatment avenues and discusses the potential challenges to clinical application.
Empagliflozin inhibits excessive autophagy through the AMPK/GSK3β signalling pathway in diabetic cardiomyopathy
Authors: Rosalinda Madonna, Stefania Moscato, Maria Concetta Cufaro, Damiana Pieragostino, Letizia Mattii, Piero Del Boccio, Sandra Ghelardoni, Riccardo Zucchi, Raffaele De Caterina
Journal: Cardiovascular Research (2023)

Abstract Aims Sodium-glucose cotransporter 2 inhibitors have beneficial effects on heart failure and cardiovascular mortality in diabetic and non-diabetic patients, with unclear mechanisms. Autophagy is a cardioprotective mechanism under acute stress conditions, but excessive autophagy accelerates myocardial cell death leading to autosis. We evaluated the protective role of empagliflozin (EMPA) against cardiac injury in murine diabetic cardiomyopathy. Methods and results Male mice, rendered diabetics by one single intraperitoneal injection of streptozotocin and treated with EMPA (30 mg/kg/day), had fewer apoptotic cells (4.9 ± 2.1 vs. 1 ± 0.5 TUNEL-positive cells %, P &amp;lt; 0.05), less senescence (10.1 ± 2 vs. 7.9 ± 1.2 β-gal positivity/tissue area, P &amp;lt; 0.05), fibrosis (0.2 ± 0.05 vs. 0.15 ± 0.06, P &amp;lt; 0.05 fibrotic area/tissue area), autophagy (7.9 ± 0.05 vs. 2.3 ± 0.6 fluorescence intensity/total area, P &amp;lt; 0.01), and connexin (Cx)-43 lateralization compared with diabetic mice. Proteomic analysis showed a down-regulation of the 5′ adenosine monophosphate-activated protein kinase (AMPK) pathway and upstream activation of sirtuins in the heart of diabetic mice treated with EMPA compared with diabetic mice. Because sirtuin activation leads to the modulation of cardiomyogenic transcription factors, we analysed the DNA binding activity to serum response elements (SRE) of serum response factor (SRF) by electromobility shift assay. Compared with diabetic mice [0.5 ± 0.01 densitometric units (DU)], non-diabetic mice treated with EMPA (2.2 ± 0.01 DU, P &amp;lt; 0.01) and diabetic mice treated with EMPA (2.0 ± 0.1 DU, P &amp;lt; 0.01) significantly increased SRF binding activity to SRE, paralleled by increased cardiac actin expression (4.1 ± 0.1 vs. 2.2 ± 0.01 target protein/β-actin ratio, P &amp;lt; 0.01). EMPA significantly reversed cardiac dysfunction on echocardiography in diabetic mice and inhibited excessive autophagy in high-glucose-treated cardiomyocytes by inhibiting the autophagy inducer glycogen synthase kinase 3 beta (GSK3β), leading to reactivation of cardiomyogenic transcription factors. Conclusion Taken together, our results describe a novel paradigm in which EMPA inhibits hyperactivation of autophagy through the AMPK/GSK3β signalling pathway in the context of diabetes.
Childhood Maltreatment and Mental Health Problems: A Systematic Review and Meta-Analysis of Quasi-Experimental Studies
Authors: Jessie R. Baldwin, Biyao Wang, Lucy Karwatowska, Tabea Schoeler, Anna Tsaligopoulou, Marcus R. Munafò, Jean-Baptiste Pingault
Journal: American Journal of Psychiatry (2023)

Childhood maltreatment is associated with mental health problems, but the extent to which this relationship is causal remains unclear. To strengthen causal inference, the authors conducted a systematic review and meta-analysis of quasi-experimental studies examining the relationship between childhood maltreatment and mental health problems.
Characteristics Associated With Refractory Course, Blindness, and Treatment Strategy–Related Outcomes in Patients With Mucous Membrane Pemphigoid
Authors: Khalaf Kridin, Nina van Beek, Elena Bühler, Anne S. Kochan, Mahdy Ranjbar, Stefan Beissert, Detlef Zillikens, Claudia Günther, Enno Schmidt
Journal: JAMA Dermatology (2023)

Mucous membrane pemphigoid (MMP) is a rare and heterogeneous subepithelial autoimmune bullous disease with predominant mucosal involvement. Characteristics associated with the disease course and complications are yet to be delineated.
Reply
Authors: Yong Lv, Guohong Han
Journal: Hepatology (2023)

We appreciate the interest of Lo in our recent study published in Hepatology.1 First, the indication of TIPS in our trial was gastroesophageal variceal bleeding occurring within the past 6 to 42 days despite the endoscopic plus nonselective beta blockers for secondary prophylaxis, which is in agreement with current practice guidelines.2 Second, we agree with Lo that the prior history of HE (hepatic encephalopathy) could increase the risk of HE after TIPS. Thus, we conducted a sensitivity analysis excluding patients with previous HE (Figure 3B in the original study).1 Nevertheless, the conclusion that concurrent embolization of large spontaneous portosystemic shunt reduced the incidence, severity and frequency of post-TIPS overt HE is not changed. Third, the survival was not significantly different in our trial. However, it should be noted that the sample size was calculated based on the primary endpoint (overt HE) and our study is not powerful enough to detect the differences of survival.1 Finally, showed that rifaximin reduced the risk of HE after TIPS when administered 15 days before the procedure and maintained 6 months after,3 while an earlier trial showed that lactulose had no such protective effect.4 In our opinion, the impact of lactulose on the post-TIPS HE merits more investigation.
Hepatic fibrosis: Targeting peroxisome proliferator-activated receptor alpha from mechanism to medicines
Authors: Lijun Gong, Fang Wei, Frank J. Gonzalez, Guolin Li
Journal: Hepatology (2023)

Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the hallmark of NASH and alcoholic steatohepatitis and can lead to cirrhosis, HCC, and liver failure. Although progress has been made in understanding the pathogenesis and clinical consequences of hepatic fibrosis, therapeutic strategies for this disease are limited. Preclinical studies suggest that peroxisome proliferator-activated receptor alpha plays an important role in preventing the development of liver fibrosis by activating genes involved in detoxifying lipotoxicity and toxins, transrepressing genes involved in inflammation, and inhibiting activation of hepatic stellate cells. Given the robust preclinical data, several peroxisome proliferator-activated receptor alpha agonists have been tested in clinical trials for liver fibrosis. Here, we provide an update on recent progress in understanding the mechanisms by which peroxisome proliferator-activated receptor alpha prevents fibrosis and discuss the potential of targeting PPARα for the development of antifibrotic treatments.
Folate, Vitamin B<sub>6</sub>, and Vitamin B<sub>12</sub>Status in Association With Metabolic Syndrome Incidence
Authors: Jie Zhu, Cheng Chen, Liping Lu, James M. Shikany, Mary E. D’Alton, Ka Kahe
Journal: JAMA Network Open (2023)

Importance The associations of B vitamin status with metabolic syndrome (MetS) incidence among the US population remain unclear. Objective To investigate intakes and serum concentrations of folate, vitamin B 6 , and vitamin B 12 in association with MetS risk in a large US cohort. Design, Setting, and Participants This prospective study included Black and White young adults in the US who were enrolled from 1985 to 1986 and studied until 2015 to 2016. Diet was assessed using a validated diet history at examination years 0, 7, and 20. Serum concentrations of folate, vitamin B 6 , and vitamin B 12 were assayed at examination years 0, 7, and 15 in a subset of 1430 participants. MetS was ascertained by clinic and laboratory measurements and self-reported medication use. Data were analyzed between January and July 2021. Exposures Intakes and serum levels of folate, vitamin B 6 , and vitamin B 12 . Main Outcomes and Measures Multivariable Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs for the associations of energy-adjusted B vitamin intakes or serum B vitamin levels with incident MetS. Results The study included 4414 participants, with 2225 Black individuals (50.4%) and 2331 women (52.8%). The mean (SD) age at baseline was 24.9 (3.6) years. A total of 1240 incident MetS cases occurred during the 30 years (mean [SD], 22.1 [9.5] years) of follow-up. Compared with the lowest quintile of each energy-adjusted B vitamin intake, the HRs for incident MetS in the highest quintile were 0.39 (95% CI, 0.31-0.49) for folate ( P for trend &amp;amp;lt; .001), 0.61 (95% CI, 0.46-0.81) for vitamin B 6 ( P for trend = .002), and 0.74 (95% CI, 0.58-0.95) for vitamin B 12 ( P for trend = .008) after adjustment for potential confounders. Similarly, significant inverse associations were observed in the subset with serum data on these B vitamins (folate: HR, 0.23; 95% CI, 0.17-0.33; P for trend &amp;amp;lt; .001; vitamin B 6 : HR, 0.48; 95% CI, 0.34-0.67; P for trend &amp;amp;lt; .001; and vitamin B 12 : HR, 0.70; 95% CI, 0.51-0.96; P for trend = .01). Conclusions and Relevance This prospective cohort study found that intakes and serum concentrations of folate, vitamin B 6 , and vitamin B 12 were inversely associated with incident MetS among Black and White young adults in the US.
Living-Donor Liver Transplant for Patients With End-stage Liver Disease
Authors: Saroja Bangaru, Hyosun Han, Kali Zhou
Journal: JAMA Surgery (2023)

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CAP and LSM as determined by VCTE are independent predictors of all-cause mortality in the US adult population
Authors: Eduardo Vilar-Gomez, Raj Vuppalanchi, Samer Gawrieh, Niharika Samala, Naga Chalasani
Journal: Hepatology (2023)

Background and Aim: Data retrospective cohort studies have shown that liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) can predict mortality in patients with NAFLD, however, its ability to predict mortality at a population level is unknown. We investigated the ability of LSM and controlled-attenuation parameter (CAP) by TE to predict mortality in a prospective US cohort. Approach and Results: A total of 4192 US adults aged ≥18 years enrolled in the National Health, and Nutrition Examination Survey (NHANES) (2017–2018) with reliable information on CAP and LSM by TE were included in this analysis. All-specific and cause-specific mortality were ascertained by linkage to National Death Index records through December 31, 2019. Cox models were used to estimate HR and 95% CI. During a mean follow-up of 24.4 months, there were 68 deaths (1.6%). CAP (adjusted HR: 1.01, 95% CI: 1.0–1.05), and LSM (adjusted HR: 1.06, 95% CI: 1.02–1.11) were independently associated with overall mortality. NAFLD by CAP ≥285 had a 2.2-fold (95% CI: 1.0–4.7) increased odds of mortality compared with non-NAFLD. Cumulative mortality rates were significantly higher in participants with LSM of 9.7–13.5 (advanced fibrosis) and LSM ≥13.6 (cirrhosis) as compared with LSM &lt;9.7; p value for trend across groups &lt;0.01. LSM ≥13.6 displayed the highest mortality risk (adjusted HR: 3.2, 95% CI: 1.3–7.8). Compared with LSM &lt;10 [absence of advanced chronic liver disease (ACLD)], LSM 10–19.9 (likely ACLD), and ≥20 kPa (likely ACLD with clinically significant portal hypertension) conferred a 3.4-fold (95% CI: 1.0–13.8) and 5.2-fold (95% CI: 1.2–22.3) increase in hazards of mortality. Conclusions: Our study findings highlight the importance of liver health as a predictor of overall mortality at a population level.
The evolving role of liver sinusoidal endothelial cells in liver health and disease
Authors: Matthew J. McConnell, Enis Kostallari, Samar H. Ibrahim, Yasuko Iwakiri
Journal: Hepatology (2023)

LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research.
Exertional Dyspnea in a Female Patient Aged 55 Years Without Significant Medical History
Authors: Sk Minhajuddin Siraj, Ritwik Ghosh, Dipayan Roy
Journal: JAMA Cardiology (2023)

This case report discusses a diagnosis of cardiac hydatid cyst in a female patient aged 55 years without significant medical history who presented with exertional dyspnea and cough for 3 months.